Herpes simplex virus type-1 (HSV-1) is an increasingly important health problem and is responsible for the majority of cases of fatal sporatic viral encephalitis and infectious blindness in the United States. Approximately 80% of the adult U.S. population is infected with HSV-I. The virus persists in a latent state in sensory neurons for the life of the host and periodically reactivates to cause frank disease. Due to the lack of an appropriate model system the molecular mechanisms controlling this important process are currently not known. One of the most common inducers of HSV reactivation in man is fever (hyperthermia). A new mouse model of induced HSV reactivation in vivo has been developed utilizing a hyperthermia based induction protocol which is simple (immersion in warm water), rapid (10 minutes), and effective (>90% reactivation rate). This model has demonstrated unequivicably that the ganglionic neuron is the reactivating cell as well as the site of infec- tious virus production. Furthermore, the fact that infectious virus can be recovered from ganglia as soon as 14 hours post treatment, (the time required for one round of acute virus replication in culture) indicates that the switch from latent to active viral gene transcription in these cells occurs very rapidly following thermal treatment. This close temporal link between thermal treatment and in vivo reactivation makes this model the first practical system in which to dissect the induction-reactivation pathway of HSV in vivo. A panel of viruses including wild type strains, mutants, specifically engineered promoter-reporter viruses, and a virally packaged vector system for in vivo promoter studies, will be employed in this system to: (1) identify the first transcripts produced upon initiation of reactivation; (2) define the promoter elements of these "Immediate Early Reactivation" genes required specifically for the initiation of transcriptional changes; and (3) characterize the roles of these and other relevant viral gene products in establishment, maintenance, and reactivation from latency. These studies will result in significant contributions to our understanding of the molecular mechanisms underlying HSV latency and reactivation, and may lead to new strategies for treatment and prevention of HSV infection.